US4637985A - Assay processes and materials therefor - Google Patents

Assay processes and materials therefor Download PDF

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Publication number
US4637985A
US4637985A US06/536,238 US53623883A US4637985A US 4637985 A US4637985 A US 4637985A US 53623883 A US53623883 A US 53623883A US 4637985 A US4637985 A US 4637985A
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United States
Prior art keywords
specific binding
assay
labelled
derivative
primidone
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US06/536,238
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English (en)
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Ahmad M. Sidki
David S. Smith
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ILS Ltd A Co OF ENGLAND
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Internationale Octrooi Maatschappij Octropa BV
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Assigned to INTERNATIONALE OCTROOI MAATSCHAPPIJ OCTROPA B.V., A COMPANY OF THE NETHERLANDS reassignment INTERNATIONALE OCTROOI MAATSCHAPPIJ OCTROPA B.V., A COMPANY OF THE NETHERLANDS ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: SIDKI, AHMAD M., SMITH, DAVID S.
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Assigned to UNILEVER PATENT HOLDINGS B.V. reassignment UNILEVER PATENT HOLDINGS B.V. CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: INTERNATIONALE OCTROOI MAATSCHAPPIJ OCTROPA B.V.
Assigned to ILS LIMITED, A COMPANY OF ENGLAND reassignment ILS LIMITED, A COMPANY OF ENGLAND ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: UNILEVER PATENT HOLDINGS B.V.,
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/536—Immunoassay; Biospecific binding assay; Materials therefor with immune complex formed in liquid phase
    • G01N33/542—Immunoassay; Biospecific binding assay; Materials therefor with immune complex formed in liquid phase with steric inhibition or signal modification, e.g. fluorescent quenching
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S436/00—Chemistry: analytical and immunological testing
    • Y10S436/80—Fluorescent dyes, e.g. rhodamine
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S436/00—Chemistry: analytical and immunological testing
    • Y10S436/807—Apparatus included in process claim, e.g. physical support structures
    • Y10S436/808—Automated or kit
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S436/00—Chemistry: analytical and immunological testing
    • Y10S436/815—Test for named compound or class of compounds
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S436/00—Chemistry: analytical and immunological testing
    • Y10S436/815—Test for named compound or class of compounds
    • Y10S436/817—Steroids or hormones
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S436/00—Chemistry: analytical and immunological testing
    • Y10S436/825—Pretreatment for removal of interfering factors from sample
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S436/00—Chemistry: analytical and immunological testing
    • Y10S436/826—Additives, e.g. buffers, diluents, preservatives

Definitions

  • This invention concerns improvements in immunoassays and other specific binding assays, and also materials suitable for carrying out the improved assays.
  • Such assays are based on the use of a labelled form of one of the specific binding partners. They are arranged so that a specific binding reaction takes place in which the proportions of the labelled form in the complexed state and the uncomplexed state at the end of the assay reaction depend on the quantity of analyte present in the system. Then the distribution of labelled material is determined by some appropriate method, involving the measurement of activity of the label in the reaction mixture or in some relevant portion thereof, e.g. the liquid or solid phase in the case of a heterogeneous reaction.
  • labels which have been used include radiolabels, enzyme labels, fluorescent labels and electron spin-resonant labels. Appropriate detectors of corresponding kinds are used to obtain a signal level dependent on the quantity of label in the measured state.
  • Such an available instrument is for example the Perkin-Elmer LS-5 (Trade Mark) luminescence spectrometer, capable of gating out detection of short-lived luminescence, and of selectively detecting light emitted within a time segment of variable width up to 13.3 milliseconds after pulse excitation of the sample.
  • Perkin-Elmer LS-5 Trade Mark luminescence spectrometer
  • the labelling substance can be chosen from a variety of stable labels, as described below.
  • a plurality of such labels also show modification of their luminescent properties upon complex formation and can thus, of desired, be made part of a single-liquid-phase, luminescence-quench time-resolved luminescence immunoassay or other binding assay, which to our knowledge has not previously been achieved.
  • the use of the quench-inhibiting substance makes it unnecessary to provide for oxygen-free conditions by such complex manipulations as bubbling with inert gas, or carrying out the measurement in vacuo.
  • luminescence measurement can last up to 13.3 milliseconds from the end of the pulse excitation.
  • Suitable luminescent substances for use in this invention may be selected from those showing O 2 -quenchable fluorescence, or phosphorescence, or both.
  • examples include halogenated derivatives, especially brominated and/or iodinated derivatives, of fluorophors. Notable examples of these are halogenated, especially brominated and/or iodinated, derivatives of fluorescein, e.g. erythrosin and eosin. Erythrosin, giving a stronger signal, is preferred to eosin.
  • fluorophors in the presence, in the reaction or measurement medium, of soluble compounds of heavy atoms, at about 1M concentration, e.g. sodium and potassium iodide, sodium or potassium bromide or iodide, caesium bromide or iodide, lead acetate, thallium acetate, or lead thallium acetate.
  • 1M concentration e.g. sodium and potassium iodide, sodium or potassium bromide or iodide, caesium bromide or iodide, lead acetate, thallium acetate, or lead thallium acetate.
  • oxygen-free conditions include, for example, the use of enzyme-substrate systems as reducing substances to reduce oxygen content of the reaction mixture or otherwise overcome the oxygen quench effect, e.g. glucose+glucose oxidase+catalase, or glucose+glucose oxidase+peroxidase substrate+peroxidase.
  • enzyme-substrate systems as reducing substances to reduce oxygen content of the reaction mixture or otherwise overcome the oxygen quench effect, e.g. glucose+glucose oxidase+catalase, or glucose+glucose oxidase+peroxidase substrate+peroxidase.
  • a detergent e.g. a non-ionic detergent such as Triton X-100 (which is a polyoxyethylenated (9-10 units/molecule) C 8 -alkylphenol), is present, for example at concentrations of the order of 1 g/l.
  • Triton X-100 which is a polyoxyethylenated (9-10 units/molecule) C 8 -alkylphenol
  • labelled materials for use in the present assays can generally be carried out in a manner analogous to the methods used to prepare labelled materials for previous binding assays.
  • erythrosin isothiocyanate and eosin isothiocyanate can be directly coupled to any of a large number of proteins and haptens needed in binding assays, using available procedures.
  • Other derivatives of luminescent labelling materials, e.g. the carboxylic acids, can be coupled using many of the widely available coupling materials.
  • an assay according to the invention comprises subjecting a sample derived from a biological fluid, such as blood serum or urine, to an immunological or other specific binding reaction with a specific binding partner of the analyte of interest, and letting the extent of this binding reaction determine the extent of complex formation by a corresponding binding material labelled with a luminescent label, and then directly or indirectly measuring by photometry the amount or distribution of the luminescent-labelled material in its free and/or complexed forms, characterised in that the labelling luminescent substance is a covalently-linked organic luminescent substance which is capable of giving delayed luminescence upon excitation by light with a wavelength greater than 400 nm (usually greater than 450 nm), and which is subject to quenching by molecular oxygen, and in that the measurement of the luminescent label is carried out by time-resolved luminescence photometry in the presence of a reducing substance, or other quench-inhibiting substance, capable of preventing quenching of the luminescence
  • the dosages of the immunoadsorbent and the luminescent-labelled analogue in such an assay are set, matched to each other and calibrated by methods well known in themselves. They are often adjusted so that about half the label (e.g. about 20-80%) remains in solution in the absence of analyte, and so that the presence of a very small incremental quantity of analyte, at the limit of sensitivity of the assay, causes a marginal quantity of label to remain in solution at the end of the binding reaction.
  • a homogeneous assay uses the following materials: (i) a specific binding partner of the analyte in soluble form, yielding a soluble binding complex with the analyte, (ii) the luminescent-labelled analogue of the analyte and (iii) the substance capable of preventing the quenching by oxygen of the luminescence from the labelled material.
  • the labelled analogue (ii) and specific binding partner (i) are selected so that their complex with each other exhibits as little luminescence as possible, e.g.
  • component (i) when component (i) is an antibody it is selected for its ability to quench the luminescence of component (ii) as completely as possible by immune complex formation, (a quenching which is exhibited also in the complete absence of oxygen). Then in this assay the measurement of luminescence can immediately follow on from the completion of the binding reaction without the step of removal of a solid phase, and the components (i) and (ii) are dosed and matched so that in the absence of analyte the luminescence of the label is about half-maximally quenched or enhanced, (e.g. about 20-80%) by binding with component (i), while the presence of a very small incremental quantity of the analyte, in the assay, causes a diminution in the degree of this quenching.
  • component (i) when component (i) is an antibody it is selected for its ability to quench the luminescence of component (ii) as completely as possible by immune complex formation, (a quenching which is exhibited also in the complete absence of oxygen). Then
  • drugs e.g. anticonvulsant/antiepileptic substances, such as primidone, phenytoin, phenobarbitone, carbamazepine, ethosuximide, valproic acid;
  • antibiotics e.g. aminoglycosides such as gentamicin, tobramycin, amikacin, netilmicin and sisomycin;
  • antiasthamatic substances e.g. theophylline
  • cardioactive or antiarrhythmic substances and related substances e.g. quinidine, propranolol, oxprenolol, procainamide and its N-acetyl metabolite, lignocaine, digoxin, digitoxin;
  • proteins and peptide hormones such as insulin, glucagon, human placental lactogen, human growth hormone, human serum albumin, immunoglobulins such as IgG, IgE, IgA, IgM, ⁇ 2 -microglobulin, thyroid-binding globulin, corticosteroid-binding globulin; hepatitis antigens and antibodies, such as HB surface antigen and corresponding antibody.
  • antibodies can be raised in known manner against their conjugates with a protein such as serum albumin.
  • a protein such as serum albumin.
  • the gate time is the time interval over which the signal is subsequently measured after each light pulse.
  • the phosphorescence of erythrosin (5 ⁇ mol/l) in buffer was measured in the presence of bovine serum albumin (BSA) or bovine thyroglobulin (BTG) (both proteins from Sigma, Poole, Dorset, U.K.).
  • BSA bovine serum albumin
  • BCG bovine thyroglobulin
  • Each carbamazepine-N-alkylamine derivative can then be reacted with erythrosin-5-isothiocyanate and the reaction mixtures separated by silica-gel thin-layer chromatography following known standard procedures.
  • Erythrosin-labelled carbamazepine products can suitably be eluted from the silica gel into methanol and stored at -20° C. until required for use, and then diluted into suitable buffer, e.g. sodium phosphate 0.1M, pH8, with 0.2% Triton X-100 and 0.3% sodium azide.
  • the concentration of T4-erythrosin can be estimated by optical density measurement after dilution in sodium phosphate buffer (100 millimolar, pH 8.0 containing 0.2% Triton X-100 and 0.3% sodium azide) assuming an extinction coefficient of 8.3 ⁇ 10 4 1 mol -1 cm -1 at 540 nm.
  • FIG. 1 shows antibody dilution curves, showing quenching of phosphorescence (one form of delayed luminescence) and delayed fluorescence (another form of delayed luminescence) of erythrosin-labelled primidone by antibodies to primidone.
  • the horizontal axis gives values of final dilution of the antibodies.
  • the vertical axis gives observed luminescence values as a percent of the value obtained without immunoglobulins present.
  • Curve A shows phosphorescence obtained in the presence of nonspecific sheep immunoglobulins (control).
  • Curve B shows delayed fluorescence, and curve C shows phosphorescence, in each case as obtained in presence of antibodies to primidone in the indicated dilution.
  • FIG. 2 shows standard curves for non-separation (homogeneous) assay of primidone in serum, with measurement of phosphorescence or delayed fluorescence of erythrosin-labelled primidone.
  • the horizontal axis gives primidone concentration (standard) (milligram/liter).
  • the vertical axis has the same significance as in FIG. 1.
  • Curves A and B represent results from phosphorescence detection and delayed fluorescence detection respectively.
  • FIG. 4 gives an antibody dilution curve showing the binding of erythrosin-labelled primidone by anti-primidone solid phase.
  • the horizontal axis indicates the amount of solid-phase particles per tube (mg).
  • the vertical axis indicates the luminescence signal as a per cent of signal as obtained in the absence of solid phase.

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  • Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Biomedical Technology (AREA)
  • Chemical & Material Sciences (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
  • Biotechnology (AREA)
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  • Cell Biology (AREA)
  • Food Science & Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Microbiology (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Analysing Materials By The Use Of Radiation (AREA)
  • Investigating Or Analysing Materials By The Use Of Chemical Reactions (AREA)
US06/536,238 1982-09-27 1983-09-27 Assay processes and materials therefor Expired - Fee Related US4637985A (en)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AT389769B (de) * 1988-06-28 1990-01-25 Koller Ernst Fluoreszenzimmunoassay auf grundlage der fluoreszenzloeschung
US5034614A (en) * 1989-06-06 1991-07-23 Director-General Of Agency Of Industrial Science And Technology Method of improving fluorescence yield
US5279943A (en) * 1985-08-02 1994-01-18 Compagnie Oris Industrie Homogeneous process for the detection and/or determination by luminescence of an analyte in a medium in which it may be present
US5346997A (en) * 1992-08-26 1994-09-13 Murphy James G Agents for complexing sodium under biological conditions
US5795784A (en) 1996-09-19 1998-08-18 Abbott Laboratories Method of performing a process for determining an item of interest in a sample
US5856194A (en) 1996-09-19 1999-01-05 Abbott Laboratories Method for determination of item of interest in a sample
US6267722B1 (en) 1998-02-03 2001-07-31 Adeza Biomedical Corporation Point of care diagnostic systems
US20040241752A1 (en) * 1998-02-03 2004-12-02 Anderson Emory V. Point of care diagnostic systems
CN117269389A (zh) * 2023-11-23 2023-12-22 成都市海通药业有限公司 一种硫酸阿米卡星注射液的质量检测方法

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0104926A3 (de) * 1982-09-27 1986-11-12 Unilever Plc Prüfungsverfahren und dafür geeignete Mittel
EP0217619A3 (de) * 1985-09-26 1989-01-25 Molecular Devices Corporation Verfahren und Vorrichtung zur Abbildung von optisch nachprüfbaren Reaktionsversuchen
FR2617974B1 (fr) * 1987-07-07 1992-11-13 Stabiligen Procede de dosage immunologique par bio- ou chimio- luminescence
JP2591089B2 (ja) * 1988-07-25 1997-03-19 松下電器産業株式会社 免疫的検出用試薬

Citations (4)

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US4160818A (en) * 1976-04-15 1979-07-10 Technicon Instruments Corporation Fluorimetric immunoassay for diphenylhydantoin
US4252783A (en) * 1979-06-18 1981-02-24 Syva Company Reducing fluorescent background in fluorescent immunoassays
EP0104926A2 (de) * 1982-09-27 1984-04-04 Unilever Plc Prüfungsverfahren und dafür geeignete Mittel
US4492762A (en) * 1981-12-11 1985-01-08 Abbott Laboratories Fluorescent polarization immunoassays

Family Cites Families (1)

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US4259313A (en) * 1978-10-18 1981-03-31 Eastman Kodak Company Fluorescent labels

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4160818A (en) * 1976-04-15 1979-07-10 Technicon Instruments Corporation Fluorimetric immunoassay for diphenylhydantoin
US4252783A (en) * 1979-06-18 1981-02-24 Syva Company Reducing fluorescent background in fluorescent immunoassays
US4492762A (en) * 1981-12-11 1985-01-08 Abbott Laboratories Fluorescent polarization immunoassays
US4492762B1 (de) * 1981-12-11 1991-08-13 Abbott Lab
EP0104926A2 (de) * 1982-09-27 1984-04-04 Unilever Plc Prüfungsverfahren und dafür geeignete Mittel

Non-Patent Citations (2)

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Title
Immuno Assays for the 80 s, Voller et al, Eds., University Park Press, Baltimore, 1981, p. 96. *
Immuno Assays for the 80s, Voller et al, Eds., University Park Press, Baltimore, 1981, p. 96.

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5279943A (en) * 1985-08-02 1994-01-18 Compagnie Oris Industrie Homogeneous process for the detection and/or determination by luminescence of an analyte in a medium in which it may be present
AT389769B (de) * 1988-06-28 1990-01-25 Koller Ernst Fluoreszenzimmunoassay auf grundlage der fluoreszenzloeschung
US5034614A (en) * 1989-06-06 1991-07-23 Director-General Of Agency Of Industrial Science And Technology Method of improving fluorescence yield
US5346997A (en) * 1992-08-26 1994-09-13 Murphy James G Agents for complexing sodium under biological conditions
US6562298B1 (en) 1996-09-19 2003-05-13 Abbott Laboratories Structure for determination of item of interest in a sample
US5795784A (en) 1996-09-19 1998-08-18 Abbott Laboratories Method of performing a process for determining an item of interest in a sample
US5856194A (en) 1996-09-19 1999-01-05 Abbott Laboratories Method for determination of item of interest in a sample
US20040241752A1 (en) * 1998-02-03 2004-12-02 Anderson Emory V. Point of care diagnostic systems
US6267722B1 (en) 1998-02-03 2001-07-31 Adeza Biomedical Corporation Point of care diagnostic systems
US6867051B1 (en) 1998-02-03 2005-03-15 Adeza Biomedical, Inc. Point of care diagnostic systems
US6936476B1 (en) 1998-02-03 2005-08-30 Adeza Biomedical Corporation Point of care diagnostic systems
US20060008923A1 (en) * 1998-02-03 2006-01-12 Anderson Emory V Point of care diagnostic systems
US20060014302A1 (en) * 1998-02-03 2006-01-19 Martinez Ricardo R Point of care diagnostic systems
US7270970B2 (en) 1998-02-03 2007-09-18 Adeza Biomedical Corporation Point of care diagnostic systems
CN117269389A (zh) * 2023-11-23 2023-12-22 成都市海通药业有限公司 一种硫酸阿米卡星注射液的质量检测方法
CN117269389B (zh) * 2023-11-23 2024-02-09 成都市海通药业有限公司 一种硫酸阿米卡星注射液的质量检测方法

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JPS59141066A (ja) 1984-08-13
EP0104926A2 (de) 1984-04-04
EP0104926A3 (de) 1986-11-12

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